Cigarette smoking causes various types of diseases with a high mobility and mortality. Yet, it is very difficult to quit smoking, largely due to nicotne dependence. Although nicotine vaccines have emerged as a possible strategy to reduce nicotine addiction the efficacy of existing nicotine vaccines has been disappointing, possibly attributed to their insufficient induction of nicotine-specific immunity. In this application, we propose to develop a new technology to rationally design and construct nicotine vaccines. Specifically, we will explore programmable DNA-nanostructures to assemble nicotine and other immunogenic components to enhance the immunogenicity and efficacy of the vaccines. To accomplish this, we will combine expertise from immunology, organic and DNA-structural chemistry, bioinformatics, and the pharmacology of nicotine addiction and behaviors. We will implement a three- phase plan, which is staggered and iterative between vaccine construction and assessment, and between immunogenicity and efficacy tests, as well as being guided by several quantitative benchmarks. Our objective is to identify 1 to 2 lead candidates by the end of the funding period, possibly advancing them towards an Investigational New Drug (IND) submission. It is conceivable that our approach can be expanded to the development of vaccines against any target of interest, including other drugs of abuse, infectious agents, and tumor antigens, thus providing a new paradigm in vaccine development.